Left ventricular noncompaction: genes and variants

Genes linked to Left ventricular noncompaction

• MYBPC3: Myosin-binding protein C, cardiac-type

  A cardiac thick-filament protein positioned in the cross-bridge region of striated muscle. It binds myosin and actin and helps tune contraction, while MYBPC3 variants are a leading genetic cause of hypertrophic cardiomyopathy.

  8 disease-causing and 154 uncertain variants in MYBPC3 are linked to Left ventricular noncompaction.

• MYH7: Myosin-7

  Its beta-myosin motor converts ATP hydrolysis into force within cardiac and slow-skeletal-muscle sarcomeres. Pathogenic variants are major causes of hypertrophic and dilated cardiomyopathy and can also produce inherited skeletal myopathies.

  2 disease-causing and 2 uncertain variants in MYH7 are linked to Left ventricular noncompaction.

• TPM1: Tropomyosin alpha-1 chain

  It lies along actin filaments and helps control access of myosin to actin in response to troponin and calcium, while also stabilizing cytoskeletal actin in nonmuscle cells. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and several congenital myopathies.

  1 disease-causing and 0 uncertain variants in TPM1 are linked to Left ventricular noncompaction.

• ACTC1: Actin, alpha cardiac muscle 1

  Its cardiac alpha-actin filaments form the core of the sarcomeric thin filament and provide the track against which myosin generates force. Pathogenic variants can cause hypertrophic or dilated cardiomyopathy and selected congenital heart defects.

  0 disease-causing and 0 uncertain variants in ACTC1 are linked to Left ventricular noncompaction.

• TNNT2: Troponin T, cardiac muscle

  It anchors the cardiac troponin complex to tropomyosin and helps translate calcium-dependent conformational changes into controlled actin-myosin interaction. Pathogenic variants can cause hypertrophic, dilated, or restrictive cardiomyopathy and alter arrhythmic risk.

  0 disease-causing and 0 uncertain variants in TNNT2 are linked to Left ventricular noncompaction.

• LDB3: LIM domain-binding protein 3

  It organizes Z-disc protein complexes and helps maintain sarcomere integrity during repeated muscle contraction. Pathogenic variants can cause myofibrillar myopathy and dilated or other forms of cardiomyopathy.

  0 disease-causing and 1 uncertain variants in LDB3 are linked to Left ventricular noncompaction.

Weakly linked (only a few uncertain records): RBM20, ACTN2, ANKRD1, DSP, KMT2D, MYL2, MYPN and TAFAZZIN.

Known disease-causing variants in Left ventricular noncompaction

Which prediction tools work for Left ventricular noncompaction

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• CADD: 88 out of 100
• AlphaGenome (regulatory): 86 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• REVEL: 83 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• AlphaMissense: 80 out of 100
• SIFT: 79 out of 100
• MetaLR: 79 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• ESM1b (LLR): 78 out of 100
• AlphaGenome (splicing): 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• PolyPhen-2: 76 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• phyloP: 74 out of 100

Same protein, different disease

• Hypertrophic cardiomyopathy is also caused by MYBPC3 variants; they fall mostly in different places as the Left ventricular noncompaction variants (19 disease-causing).
• Hypertrophic cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Left ventricular noncompaction variants (239 disease-causing).
• Dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Left ventricular noncompaction variants (21 disease-causing).
• Primary dilated cardiomyopathy is also caused by MYH7 variants; they fall mostly in different places as the Left ventricular noncompaction variants (15 disease-causing).
• Myosin storage myopathy is also caused by MYH7 variants; they fall mostly in different places as the Left ventricular noncompaction variants (13 disease-causing).
• MYH7-related skeletal myopathy is also caused by MYH7 variants; they fall mostly in different places as the Left ventricular noncompaction variants (7 disease-causing).
• Hypertrophic cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Left ventricular noncompaction variants (15 disease-causing).
• Primary dilated cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Left ventricular noncompaction variants (6 disease-causing).
• Dilated cardiomyopathy is also caused by TPM1 variants; they fall mostly in different places as the Left ventricular noncompaction variants (6 disease-causing).

Diseases related to Left ventricular noncompaction

• Hypertrophic cardiomyopathy, also linked to ACTC1, LDB3, MYBPC3, MYH7 and 2 more
• Dilated cardiomyopathy, also linked to ACTC1, LDB3, MYBPC3, MYH7 and 2 more
• Primary dilated cardiomyopathy, also linked to ACTC1, MYBPC3, MYH7, TNNT2 and 1 more
• Familial isolated dilated cardiomyopathy, also linked to ACTC1, MYH7, TNNT2 and TPM1
• Primary familial dilated cardiomyopathy, also linked to LDB3, MYH7 and TNNT2
• Atrial septal defect, also linked to ACTC1 and TPM1
• Primary familial hypertrophic cardiomyopathy, also linked to MYBPC3 and MYH7
• Familial cardiomyopathy, also linked to MYH7 and TPM1
• Cardiomyopathy, familial restrictive, 3, also linked to TNNT2
• Myofibrillar myopathy, also linked to LDB3
• Myosin storage myopathy, also linked to MYH7
• Restrictive cardiomyopathy, also linked to MYH7

Frequently asked questions

Which genes are linked to Left ventricular noncompaction?

In CATVariant, Left ventricular noncompaction is linked to 6 analyzed proteins: MYBPC3 (Myosin-binding protein C, cardiac-type), MYH7 (Myosin-7), TPM1 (Tropomyosin alpha-1 chain), ACTC1 (Actin, alpha cardiac muscle 1), TNNT2 (Troponin T, cardiac muscle) and LDB3 (LIM domain-binding protein 3).

How many genetic variants are linked to Left ventricular noncompaction?

331 variants: 11 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 162 are of uncertain significance or have conflicting reports.

Which uncertain variants in Left ventricular noncompaction look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Left ventricular noncompaction?

Among tools not trained on clinical labels, CADD separates this disease's known disease-causing variants from harmless ones best (AUROC 0.88, based on 9 disease-causing and 1163 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

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